Ischemic acute renal failure (ARF) remains an important cause of morbidity and mortality in hospitalized patients. To define the cellular and molecular factors responsible for ischemic injury and repair, this laboratory has studied genes whose expression is modified in the postischemic kidney. One of the proteins which we named Kidney Injury Molecule-1 (KIM-1) is markedly upregulated in proximal tubular epithelial cells of the S3 segment where most of the damage and repair occurs. KIM-1 is a cell membrane glycoprotein containing an immunoglobulin (Ig)-like domain and a mucin domain in its extracellular portion, and its expression in the postischemic kidney is also co-localized with the de-differentiation marker vimentin and proliferation marker bromodeoxyuridine. In order to study the functions of KIM-1, this laboratory has generated a fusion protein containing the full length of KIM-1 extracellular region including both mucin and Ig domains fused to the Fc part of immunoglobulin, a KIM-1 gene transfer system using baculovirus, and multiple KIM-1 antibodies. In a pilot study KIM-1 fusion protein was found to reduce proximal tubular cell adhesion to fibronectin in a new cell adhesion system developed in this laboratory. I hypothesize that KIM-1 plays an important role in ischemic renal injury and repair. I will examine the role of KIM-1 on cell-cell and cell-matrix adhesion, as well as cell migration and proliferation in cultured proximal tubular cells and in vivo. Studies in vitro will be carried out by overexpressing KIM-1 by baculovirus and by using blocking antibodies against KIM-1. I will also examine which functional domains are involved by deletion and mutagenesis. Finally I will examine the effect of KIM-1 on dedifferentiation, proliferation and functional defects postischemia in vivo by studying KIM-1 knockout mice. This will help us to better understand the cellular and molecular mechanism involved in renal proximal tubular injury and repair processes and may ultimately lead to new diagnostic and therapeutic approaches in ARF.